Worldwide Genetic Variation at the 3'-UTR Region of the LDLR Gene: Possible Influence of Natural Selection

The low density lipoprotein receptor gene (LDLR) contains many Alu insertions, and is especially Alu‐rich at its 3′‐untranslated region (3′‐UTR). Previous studies suggested that the LDLR 3′‐UTR could regulate gene expression by the stabilization of its mRNA. Given the faster Alu evolutionary rate, and wondering about its consequences in a possibly regulatory locus, we have studied ～800 bp of 222 chromosomes from individuals of African, Asian, Caucasian and Amerind ancestry, to better understand the evolution of the worldwide genetic diversity at this locus. Twenty‐one polymorphic sites, distributed in 15 haplotypes, were found. High genetic diversity was observed, concentrated in one Alu insertion (Alu U), which also shows a fast evolutionary rate. Genetic diversity is similar in all populations except Amerinds, suggesting a bottleneck during the peopling of the American continent. Three haplotype clusters (A, B, C) are distinguished, cluster A being the most recently formed (～500,000 years ago). No clear geographic structure emerges from the haplotype network, the global F_st (0.079) being lower than the average for the human genome. When ancestral population growth is taken into account, neutrality statistics are higher than expected, possibly suggesting the action of balancing selection worldwide.     

Expression, Genomic Structure and Mapping of the Thymus Specific Protease Prss16: A Candidate Gene for Insulin Dependent Diabetes Mellitus Susceptibility

PRSS16 is a serine protease specifically expressed by epithelial cells in the thymic cortex. The human gene is encoded on 6p21.3-p22 where recent linkage analysis has identified an association with insulin dependent diabetes mellitus (IDDM) susceptibility independent of HLA-DR3. To further investigate its potential role in autoimmunity, we characterized the mouse orthologue, Prss16. The genomic structure of Prss16 shows conservation with the human gene in size, number of exons and chromosomal location. Mapping of Prss16 places it on mouse chromosome 13 centromeric of thesatin locus. This region is comparable to the PRSS16 region on human chromosome 6 and has also been linked to quantitative trait locus for IDDM in the nonobese diabetic mouse. Similar to the human gene, Prss16 expression is highly specific in the mouse with expression limited to the cortical thymic epithelium. Notably, embryonic expression coincides with population of the thymic anlage with T-cell precursors and initiation of T-cell development. We also show that NOD and New Zealand Black mice, which have a disrupted thymic architecture and autoimmune phenotype, have lower levels of Prss16 expression compared to C57BL/6 mice. These findings support the role of Prss16 in T-cell development and susceptibility to autoimmunity in the mouse.